1. Technical Field of the Invention
The present invention relates generally to the therapy of Celiac Disease, Crohn's Disease, and Ulcerative Colitis (collectively referred to as Inflammatory Bowel Disease, or IBD). The invention is more specifically related to antagonists of type-1 interferon as well as to therapeutic methods employing such antagonists for the treatment of IBD.
2. Description of Related Art
Celiac Disease, Crohn's Disease, and Ulcerative Colitis (collectively referred to as Inflammatory Bowel Disease, or IBD) are chronic, inflammatory diseases of the gastrointestinal tract. While the clinical features vary somewhat between these two disorders, both are characterized by abdominal pain, diarrhea (often bloody), a variable group of ‘extra-intestinal’ manifestations (such as arthritis, uveitis, skin changes, etc) and the accumulation of inflammatory cells within the small intestine and colon (observed in pathologic biopsy or surgical specimens).
IBD affects both children and adults, and has a bimodal age distribution (one peak around 20, and a second around 40). IBD is a chronic, lifelong disease, and is often grouped with other so-called “autoimmune” disorders (e.g. rheumatoid arthritis, type I diabetes mellitus, multiple sclerosis, etc). IBD is found almost exclusively in the industrialized world. The most recent data from the Mayo Clinic suggest an overall incidence of greater than 1 in 100,000 people in the United States, with prevalence data in some studies greater than 1 in 1000. There is a clear trend towards an increasing incidence of IBD in the US and Europe, particularly Crohn's Disease. The basis for this increase is not presently clear. As such, IBD represents the 2nd most common autoimmune disease in the United States (after rheumatoid arthritis).
Type 1 interferons have been detected in the gut of patients with Inflammatory Bowel Disease. For example, interferon alpha was reported to be overexpressed in the gut mucosa of patients with Celiac Disease, a gluten-sensitive enteropathy, and in the lamina propria of Crohn's Disease patients. Monteleone et al., Gut 48:425-429 (2001); Fais et al., J. Interferon Res. 14:235-238 (1994). The biological significance of the type 1 interferons in the tissues from these disease patients has not been described. Type 1 interferons have not been described in the circulation of individuals with Inflammatory Bowel Disease and it is unclear what role, if any, interferon alpha plays in the pathology of these diseases.
Type 1 interferons (i.e. interferons alpha and beta) are multifunctional cytokines that play a critical role in a variety of immune response systems. Abnormal production of type 1 interferons is associated with several pathological conditions including transplant rejection and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and insulin dependent diabetes. The biological effects of type 1 interferons are mediated through a single cell-surface receptor (IFNAR) that binds to all of the type 1 interferons but not to the type 2 interferon, interferon-γ. The type 1 interferon receptor is expressed at varying levels on all nucleated cells in the body. It is composed of two polypeptide chains designated IFNAR1 and IFNAR2, that, together, constitute the high-affinity receptor capable of transducing an intracellular signal upon interferon binding.
A mouse monoclonal antibody, designated 64G12, directed against the IFNAR1 chain of the human type 1 interferon receptor, has been shown to block the activity of type 1 interferons by interfering with the binding of the cytokines to their receptor. (See, U.S. Pat. Nos. 5,889,151, 5,886,153, 5,731,169, 5,861,258, and 5,919,453, and 6,475,983, as well as U.S. Patent Application Publication No. 20020055492, each of which is incorporated by reference herein in its entirety). In primate transplantation models, 64G12, given in conjunction with cyclosporine, has provided remarkable long-term efficacy in prevention of skin allograft rejection and graft-versus host disease. Benizri et al., J. Interferon Cytokine Res. 18:273 (1998).
Treatment of IBD is varied. First line therapy typically includes salicylate derivatives (e.g., 5-ASA) given orally or rectally. Response rates in uncomplicated Crohn's Disease are approximately 40% (compared to 20% for placebo). Corticosteroids remain a mainstay in the treatment of patients with more “refractory” disease, despite the untoward side-effects. Newer treatment options include anti-metabolites (e.g., methotrexate, 6-mercaptopurine) and immunomodulators (e.g., Remicade—a chimeric human antibody directed at the TNFα receptor).
In spite of considerable research into therapies for these disorders, Celiac Disease, Crohn's disease and ulcerative cholitis remain difficult to treat effectively. Accordingly, there remains an unmet need in the art for improved methods for treating such Inflammatory Bowel Diseases. The present invention fulfills these and other related needs.